Adaptive Clinical Trial Design: An Overview and Potential Applications in Dermatology

Elman, Scott A.; Ware, James H.; Gottlieb, Alice B.; Merola, Joseph F.

doi:10.1016/j.jid.2016.02.807

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…We hypothesized that honey would be safe and clinically more effective at controlling this disorder than a placebo. Since no prior information could assist us at estimating the effect sizes and associated variances of placebo and honey in treating canine intertrigo, we circumvented the problem of arbitrarily fixing sample sizes by using an adaptive group-sequential design [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Medical honey for canine nasal intertrigo: A randomized, blinded, placebo-controlled, adaptive clinical trial to support antimicrobial stewardship in veterinary dermatology

et al. 2020

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Intertrigo is a skin fold dermatitis often requiring recurrent treatment with topical antiseptics or antibiotics, which can select antimicrobial resistance. To minimize this risk, we tested the effectiveness of medical-grade Manuka honey at treating intertrigo as compared to a placebo hydrogel. We additionally characterized the culturable microbial flora of intertrigo and recorded any adverse effect with either treatment. During this randomized, placebo-controlled, double-blinded, adaptive group-sequential trial, the owners washed the affected sites on their dog with water, dried and applied a thin film of either the honey or the placebo product once daily for 21 days. Cytological and lesional composite scores, owner-assessed pruritus, and microbial cultures were assessed prior to treatment and on Day-22. The fixed effects of time, treatment, and animal-related variables on the pruritus and on each composite score, accounting for random dog effect, were estimated separately with generalized linear mixed models for repeated count outcomes (α = 0.05). The null hypothesis of equal treatment effects was rejected at the first interim analysis. The placebo (n = 16 dogs) outperformed the medical honey (n = 13 dogs) at improving both the cytological score (Treatment×Time = -0.35±0.17; P = 0.04) and clinical score (Treatment×Time = -0.28±0.13; P = 0.04). A microbial burden score higher than 4 increased the severity of the cytological score (dichotomous score: 0.29±0.11; P = 0.01), which in turn increased the severity of the clinical score and pruritus score. For every unit increase in cytological score, the linear predictor of clinical score increased by 0.042±0.019 (P = 0.03), and the one of pruritus score increased by 0.12±0.05 (P = 0.01). However, medical honey outperformed the placebo at alleviating the dog’s owner-assessed pruritus after statistically controlling for masking effects (Time = -0.94±0.24; P = 0.002; and Treatment×Time = 0.80±0.36; P = 0.04). Unilateral tests of the least-square mean estimates revealed that honey only significantly improved the pruritus (Hommel-adjusted P = 0.003), while the placebo only improved the cytological and clinical scores (Hommel-adjusted P = 0.01 and 0.002, respectively). Taken together, these results question the value of Manuka honey at treating nasal intertrigo in dogs.

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Section: Discussionmentioning

confidence: 99%

Medical honey for canine nasal intertrigo: A randomized, blinded, placebo-controlled, adaptive clinical trial to support antimicrobial stewardship in veterinary dermatology

et al. 2020

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“…The review found some key publications that discussed why the reporting of AD trials requires special consideration and reporting suggestions or recommendations for particular types of AD trials [ 23 , 25 , 33 , 34 , 38 , 45 , 51 , 53 – 61 ]. ADs are not immune to potential biases and limitations despite their appealing nature and promising benefits [ 9 , 50 , 53 ].…”

Section: Methodsmentioning

confidence: 99%

Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design

Dimairo

Coates

Pallmann

et al. 2018

BMC Med

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BackgroundAdequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline.MethodsWe developed the guideline in seven overlapping stages:Building on prior research to inform the need for a guideline;A scoping literature review to inform future stages;Drafting the first checklist version involving an External Expert Panel;A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders;A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document;Refining and finalising the checklist; andWriting-up and dissemination of the E&E document.The CONSORT Executive Group oversaw the entire development process.ResultsDelphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies.ConclusionsWe hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1196-2) contains supplementary material, which is available to authorized users.

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Section: Adaptive Design Of the Phase Iib Trials For Rozibafusp Alfa ...mentioning

confidence: 99%

“…Futility interim analyses increase the efficiency of a trial by supporting early decision making to terminate a futile trial. This can reduce the cost of failure and release patients and SLE-experienced sites for other development programmes that may show benefit, 44 as well as reduce potential safety risks to participating patients. 41 44 45 Bayesian hierarchical modelling An innovative feature of the phase IIb study design is a prespecified analysis to evaluate the primary endpoint, which is based on a binary outcome (responder vs nonresponder; figure 1).…”

Section: Futility Evaluationsmentioning

confidence: 99%

“…However, in SLE and other inflammatory diseases, a monotonic dose-response is often not observed (a phenomenon that has been documented for other therapeutics that modulate a complex immune system with many feedback loops and compensatory mechanisms). [44][45][46][47][48][49][50] Instead of requiring a larger trial to accommodate the uncertainty as to the optimal dose, the innovative phase IIb design uses a Bayesian hierarchical model to compare each of the three dose levels to placebo. 51 52 With this approach, the statistical model can borrow information across doses based on observed similarities between results (treatment effects) for various treatment groups.…”

Section: Futility Evaluationsmentioning

confidence: 99%

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Improving resource utilisation in SLE drug development through innovative trial design

et al. 2023

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SLE is a complex autoimmune disease with considerable unmet need. Numerous clinical trials designed to investigate novel therapies are actively enrolling patients straining limited resources and creating inefficiencies that increase enrolment challenges. This has motivated investigators developing novel drugs and treatment strategies to consider innovative trial designs that aim to improve the efficiency of generating evidence; these strategies propose conducting fewer trials, involving smaller numbers of patients, while maintaining scientific rigour in safety and efficacy data collection and analysis. In this review we present the design of two innovative phase IIb studies investigating efavaleukin alfa and rozibafusp alfa for the treatment of SLE which use an adaptive study design. This design was selected as a case study, investigating efavaleukin alfa, in the Food and Drug Administration’s Complex Innovative Trial Design Pilot Program. The adaptive design approach includes prospectively planned modifications at predefined interim timepoints. Interim assessments of futility allow for a trial to end early when the investigational therapy is unlikely to provide meaningful treatment benefits to patients, which can release eligible patients to participate in other—potentially more promising—trials, or seek alternative treatments. Response-adaptive randomisation allows randomisation ratios to change based on accumulating data, in favour of the more efficacious dose arm(s), while the study is ongoing. Throughout the trial the placebo arm allocation ratio is maintained constant. These design elements can improve the statistical power in the estimation of treatment effect and increase the amount of safety and efficacy data collected for the optimal dose(s). Furthermore, these trials can provide the required evidence to potentially serve as one of two confirmatory trials needed for regulatory approval. This can reduce the need for multiple phase III trials, the total patient requirements, person-exposure risk, and ultimately the time and cost of investigational drug development programmes.

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Adaptive Clinical Trial Design: An Overview and Potential Applications in Dermatology

Cited by 7 publications

References 29 publications

Medical honey for canine nasal intertrigo: A randomized, blinded, placebo-controlled, adaptive clinical trial to support antimicrobial stewardship in veterinary dermatology

Medical honey for canine nasal intertrigo: A randomized, blinded, placebo-controlled, adaptive clinical trial to support antimicrobial stewardship in veterinary dermatology

Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design

Improving resource utilisation in SLE drug development through innovative trial design

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